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MC-IRG - International Re-integration Grants (IRG)

Cel

Small heat shock proteins (sHSPs) are a family of proteins that play a crucial role in the cell. The sHSPs bind to proteins that have partially unfolded and prevent them from forming deleterious intracellular aggregates. In humans high levels of sHSPs are found in various tissues. Aberrant sHSP activity, or the loss of it, is associated with a variety of diseases including cataract, myopathy and neurodegenerative diseases. Additionally, high levels of sHSPs protect cancer cells from chemotherapeutic treatment. To understand how sHSPs function a detailed knowledge of their 3D structure is required, both free and bound to a substrate. In this work we plan to study the structures of two human sHSPs, HSPB6 and HSPB8, by X-ray crystallography, small angle X-ray scattering and other biophysical methods. In the past isolated human sHSPs have proven recalcitrant to crystallization, we will circumvent this problem by studying HSPB6 and HSPB8 bound to known partner proteins. This work will be complemented with detailed structural studies of their interaction with ATXN3, a model protein substrate for polyglutamine expansion associated neurodegenerative diseases. We plan to generate atomic resolution structures of these various complexes that can be used to define the critical regions of the sHSPs that are necessary for activity. This knowledge, in turn, can be used to design therapeutic compounds that mimic or modulate sHSP function.